This project will investigate the clinical pharmacology of the indirectly acting sympathomimetic psychostimulant methamphetamine and its enantiomers. Methamphetamine abuse is increasing and is associated with HIV transmission and violence. Currently, the dextrorotatory (also called d, (+) or S) isomer of methamphetamine is the illicit form available in most communities. Recent regulatory changes in the availability of synthetic precursors suggest that d-methamphetamine use may decrease and racemic (a 50:50 mixture of d/1) methamphetamine use may increase. We will evaluate pharmacokinetic and dynamic interactions of racemic and optically pure methamphetamine and interactions with a serotonin reuptake inhibitor on drug metabolism, cardiovascular, neuropsychologic, and subjective effects using enantiomer-specific assays, deuterium-labeled methamphetamine and analogs. We predict that 1) the d-isomer of methamphetamine will be more potent in producing CNS stimulation than the l-isomer; 2) the l-isomer will be metabolized more slowly than the d-isomer with a greater percentage of the l-4-hydroxy metabolite excreted in urine; 3) with repeated administration of the racemic mixtures, the l-isomer will accumulate in the body; 4) both isomers will increase heart rate and systemic and pulmonary systolic and diastolic pressures, but the l-isomer will be relatively more potent; 4) the effects of methamphetamine will be attenuated by a SSRI; and 5) methamphetamine clearance can be competitively inhibited by agents metabolized by CYP2D6. Four separate studies will be carried out in human volunteers experienced with methamphetamine effects. Primary outcome measures include drug and metabolite measurements in plasma and urine and subjective and cardiovascular measures, including 2D echocardiography.